PACAP signaling in stress and anxiety

项目总结/摘要 暴露在压力下会导致精神疾病，包括焦虑症。的机制 人们不了解压力诱发这些疾病的原因，这些疾病往往是持久性的，而且难以治疗。 最近的研究表明，压力激活和修改PACAP（垂体腺苷酸环化酶激活 多肽）系统。模拟压力诱导的PACAP功能增加， PACAP治疗会导致持续（持续超过1周）的声音惊吓增加，这是一种经常 用于焦虑症的临床前和临床研究。相比之下，单一CRF治疗导致 在24小时内使其正常化。PACAP能够产生长期增加焦虑相关 大鼠的行为将其与CRF区分开来，并使其成为应激研究的重要新靶点。的确， 新的证据表明，PACAP参与了严重和衰弱形式的焦虑的发展 在人类中，包括创伤后应激障碍（PTSD），其中一个关键标志是持续增加， 惊吓（过度觉醒）。该提案研究了压力和焦虑中PACAP信号传导的神经生物学， 老鼠的相关行为考虑到迫切需要新的治疗方法来治疗与压力有关的疾病，目标1 将专注于确定新类别的代理，可以阻止急性和/或长期的行为影响， PACAP。我们将研究PACAP拮抗剂，其对PACAP（PAC 1）受体具有高度选择性，但对PACAP（PAC 1）受体没有选择性。 之前在压力研究中进行过测试，以及κ-阿片受体（KOR）拮抗剂，已被证明 阻止压力的长期影响。这些研究可能会加速药物开发，同时提供新的 机械研究方向。目标2将研究PACAP产生持久性 方面的影响.最初的研究将集中在终纹床核（BNST），因为（i）BNST是一个 PACAP神经支配的主要靶点，（ii）应激增加BNST中PACAP的表达，以及（iii）输注 PACAP直接进入BNST足以产生持久的过度觉醒。一组研究将 研究增强或破坏CREB（腺苷酸环化酶的下游靶点）的功能如何影响 基线和PACAP增强惊吓。平行研究将扩展我们的新数据，表明PACAP，但不是 CRF引起microRNA 134（miR 134）的显著下调，miR 134是一种非编码RNA， 脊柱密度和体积，通过检查增强或破坏miR 134功能如何影响基线， PACAP增强惊吓。这些研究可以确定细胞内的过程，可以针对 药物开发。目标3将确定PACAP是否会产生PTSD的其他核心症状，包括 持续的快感缺乏、社交退缩、注意力不集中和恐惧消退障碍的迹象。 这些研究可以确定PACAP给药提供了一种更全面的方法， 模拟了创伤后应激障碍的各种症状，这一发现也将促进药物的开发。总的来说， 所提出的工作可能产生对抗应激剂的开发有用的知识。

PROJECT SUMMARY/ABSTRACT Exposure to stress can cause psychiatric illnesses including anxiety disorders. The mechanisms by which stress induces these illnesses, which tend to be both persistent and resistant to treatment, are not understood. Recent work shows that stress activates and modifies PACAP (pituitary adenylate cyclase-activating polypeptide) systems in the rat brain. Mimicking stress-induced increases in PACAP function with a single PACAP treatment causes persistent (lasting more than 1 week) increases in acoustic startle, a measure often used in both preclinical and clinical studies of anxiety. In contrast, a single CRF treatment causes increases in startle that normalize within 24 hr. PACAP's ability to produce long-lasting increases in an anxiety-related behavior in rats differentiates it from CRF and makes it an important new target for stress research. Indeed, new evidence suggests that PACAP is involved in the development of severe and debilitating forms of anxiety in humans, including post-traumatic stress disorder (PTSD), a key sign of which is persistent increases in startle (hyperarousal). This proposal examines the neurobiology of PACAP signaling in stress- and anxiety- related behaviors in rats. Considering the urgent need for new treatments for stress-related disorders, Aim 1 will focus on identifying new classes of agents that can block the acute and/or long-lasting behavioral effects of PACAP. We will examine PACAP antagonists, which are highly selective for PACAP (PAC1) receptors but not previously tested in stress studies, and kappa-opioid receptor (KOR) antagonists, which have been shown to block the long-term effects of stress. These studies may hasten medication development while providing new directions for mechanistic research. Aim 2 will examine the mechanisms by which PACAP produces persistent effects. Initial studies will focus on the bed nucleus of the stria terminalis (BNST) because (i) the BNST is a major target of PACAP innervation, (ii) stress increases PACAP expression in the BNST, and (iii) infusion of PACAP directly into the BNST is sufficient to produce long-lasting hyperarousal. One set of studies will examine how enhancing or disrupting the function of CREB, a downstream target of adenylate cyclase, affects baseline and PACAP-enhanced startle. Parallel studies will extend our new data showing that PACAP but not CRF causes marked downregulation of microRNA134 (miR134), a non-coding RNA that negatively regulates spine density and volume, by examining how enhancing or disrupting miR134 function affects baseline and PACAP-enhanced startle. These studies may identify intracellular processes that can be targeted for medication development. Aim 3 will determine if PACAP produces other core symptoms of PTSD, including persistent signs of anhedonia, social withdrawal, deficits in concentration, and impairments in extinction of fear. These studies may establish that PACAP administration provides an approach that more comprehensively models the myriad symptoms of PTSD, a finding that would also facilitate medication development. Overall, the proposed work may yield knowledge useful for the development of anti-stress agents.